Relapse is one of the most serious challenges facing long-term management of cocaine addiction. Clinical evidence points to initial re-exposure to cocaine (priming), stimuli associated with previous cocaine use, and stress as triggers of relapse in people. The same triggers induce reinstatement of cocaine seeking in laboratory animals, providing potentially useful models for investigating the biological basis of relapse. As a relatively nonselective inhibitor of dopamine (DAT), norepinephrine (NET), and serotonin transport (SERT), cocaine acts as an indirect agonist in all three monoamine systems. Compelling evidence supports a role for DA mechanisms in priming- and stimulus-induced reinstatement of cocaine seeking, and emerging data in nonhuman primates suggest that both NE and 5-HT mechanisms play significant modulatory roles. Inhibition of NET appears to be primarily facilitative with respect to reinstatement of cocaine seeking, whereas inhibition of SERT appears to be primarily inhibitory. Stress-induced reinstatement of drug seeking also appears to have a prominent NE component as well as a component mediated by central corticotropin releasing factor (CRF). Our proposed research will use nonhuman primate models developed previously under this grant to investigate the role of specific NE, 5-HT and CRF receptor subtypes in the reinstatement of drug seeking induced by a cocaine-paired stimulus alone and combined with cocaine priming and by pharmacological and ethologically-based stress. Specific Aim 1 will use selective NET inhibitors and selective NE agonists and antagonists to investigate the role of a1 and [unreadable] receptor mechanisms in the reinstatement of drug seeking following extinction of cocaine self-administration and after a comparable period of cocaine abstinence without explicit extinction of the operant response. Specific Aim 2 will use a conceptually similar strategy to investigate the role of a2 and CRF1 mechanisms in stress- induced reinstatement of cocaine seeking resulting from intruder confrontation and administration of yohimbine. Cross-over studies with those in Specific Aim 1 will determine the degree to which unique and overlapping mechanisms mediate priming- and stimulus-induced reinstatement of cocaine seeking compared to stress-induced reinstatement of cocaine seeking. Specific Aim 3 will use selective SERT inhibitors and selective agonists/antagonists to investigate the role of 5-HT1A and 5-HT2C mechanisms in 5-HT-mediated inhibition of reinstated cocaine seeking. Control studies involving reinstatement of food-seeking behavior and quantitative behavioral observations will determine the specificity with which drugs affect the reinstatement of cocaine seeking without inducing generalized disruptive effects. The proposed research will test specific hypotheses regarding NE, 5-HT and CRF mechanisms underlying reinstated cocaine seeking and provide pertinent information about potential pharmacological targets for the management of relapse.